Monoclonal antibody 9.2.27 combined with effector cells effectively destroyed large established human melanoma tumors in nude mice. The type of effector cells responsible for this tumor destruction are natural killer (NK) cells. The antigen specifically recognized by Mab 9.2.27 on human melanoma cells is a non-cartilage chondroitin sulfate proteoglycan. Extensive pulse-chase analyses identified key events in the biosynthesis, intracellular transport, and cell surface expression of this antigen and indicated that a low pH mechanism within Golgi-related compartments constitutes a post-translational sorting mechanism which specifies the amount of proteoglycan to be expressed on the cell surface or exocytosed by the melanoma cell. Monoclonal antibodies to the disialogangliosides GD2 and GD3 showed that these glycolipids are localized in adhesion plaques on the surface of melanoma cells involved in interaction with solid substratum. More specifically, these glycolipids are directly involved in the binding of melanoma cells to the cell attachment site of fibronectin. Another monoclonal antibody highly specific for melanoma was shown to react specifically with the 9-0-acetyl group of the terminal sialic acid of GD[unreadable]2[unreadable] and increased production of an acetyl-transferase responsible for this modification was found in human melanoma cells. In addition, several monoclonal antibodies of IyG3 isotype, directed to GD[unreadable]3[unreadable], were able to destroy established human melanoma tumors in nude mice when combined with suitable effectors that appear to be mainly cells with natural killer (NK) activity. GD[unreadable]3[unreadable] also has been found considerably better expressed on the surface of highly metastatic melanoma cells than on primary lesions of the same type, providing some hope that these markers may provide effective antigen targets for immunotherapy of malignant melanoma. Taken together, our results strongly suggest that monoclonal antibodies to chemically well-defined cell surface antigens expressed on melanoma cells provide excellent molecular probes to determine the fine structure of these molecules and also serve as effective targeting devices for more effective destruction of human melanoma tumors in vivo. (AB)